2-(2-amino-2-acetamido) acetamido-benzophenones



July 30, 1968 s. c. BELL ET AL 3,395,181

2 2 AMINO 2-ACETAMIDO) ACETAMIDOBEN ZOPHENONES 6 0M CH-NH NHZ OriginalFiled Nov. 50, 1964 CH-NH2 c CH3 IN VE/V TORS STANLEY C. BELL SCOTT J.CHILDRESS By 4 Mw A 7' TOR/VE Y United States Patent 3,395,1812-(2-AMlN0-2-ACETAMIDO) ACETAMIDO- BENZOPHENONES Stanley C. Bell, PennValley, and Scott J. Childress,

Philadelphia, Pa., assignors to American Home Products Corporation, NewYork, N.Y., a corporation of Delaware Application Nov. 30, 1964, Ser.No. 414,583, new Patent No. 3,344,136, dated Sept. 26, 1967, which is acontinuation-impart of application Ser. No. 327,674, Dec. 3, 1963.Divided and this application Mar. 6, 1967, Ser. No. 621,034

2 Claims. (Cl. 260-562) ABSTRACT OF THE DISCLOSURE Benzophenonessubstituted at the 2-position with a (2 amino-Z-acetamido) acetamidogroup are prepared by reacting ammonia with benzophenones substituted atthe 2 position with a 2 (N-acetoxyacetamido)acetamido group. The 2(Z-aminO-Z-acetamido)acetamido benzophenones are used as intermediatesfor the preparation of 1,3 dihydro 2H-1,4-benzodiazepin-2-ones of valuein medicine as anti-convulsants, sedatives, and muscle-relaxants.

This application is a division of Ser. No. 414,583 filed Nov. 30, 1964,now U.S. Patent 3,344,136 which is a continuation-in-part of applicationSer. No. 327,674 filed Dec. 3, 1963, now abandoned.

This invention relates to compositions of matter classified in the artof chemistry as substituted benzodiazepines, to intermediates for theirmanufacture and to processes for making and using them.

The invention sought to be patented in its principal process aspectresides in the concept of heating a composition of matter in which thebenzophenone nucleus has attached thereto the2-(N-acetoxyacetamido)acetamido radical in the 2-position, with ammoniain a non-reactive polar solvent to produce a S-acetamido-l,3-dihydro--phenyl-ZH-1,4-benzodiazepin-2-one.

The invention sought to be patented in a further process aspect residesin the concept of a sequence of reactions including: heating acomposition of matter in which the benzophenone nucleus has attachedthereto the 2- (N-acetoxyacetamido) acetam'ido radical in the2-position, with ammonia in a nonreactive polar solvent to produce a3-acetamido-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-Z-one and,hydrolizing the 3-acetamido compound so-produced to produce a3-amino-l,3-dihydro-5- phenyl-ZH-l,4-benzodiazepin-2-one.

The invention sought to be patented in the further pr0cess aspect alsoresides in the concept of the individual step of the foregoing sequenceof reactions including: hydrolizing a3-acetamido-1,3-dihydro-5-phenyl-2H-1,4- benzodiazepin-Z-one to producea 3-amino-1,3-dihydro-5 phenyl-ZH-1,4-benzodiazepin-2-one.

The invention sought to be patented in another process aspect resides inthe concept of mixing a composition of matter in which the benzophenonenucleus has attached thereto the Z-(N-acetoxyacetamido)acetamido radicalin the 2-position with ammonia in a non-reactive polar solvent withoutheating, and allowing the product so obtained to stand dissolved in asolvent until 3-acetamido-1,3-dihydro 5phenyl-ZH-1,4-benzodiazepin-2-one is precipitated.

The invention sought to be patented in a principal composition aspect isdescribed as residing in the concept of a chemical compound having themolecular structure of 3acylamido-l,3-dihydro-S-phenyl-2H-1,4-benzodiazepin- 2-one.

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The tangible embodiments of the principal compositions of the inventionpossess the inherent general physical properties of being relativelyhigh melting, white crystalline solids; are substantially insoluble inwater and are soluble in polar solvents, such as lower aliphaticalcohols. Examination of the compounds produced according to thehereinafter described process reveals, upon ultra-violet and infraredspectrographic analysis, spectral data confirming the molecularstructure herein-before set forth. Thus the frequency of the exocyclicamino group in the 3-position is evident. The aforementioned physicalcharacteristics, taken together with the nature of the startingmaterials and the mode of synthesis, positively confirm the structure ofthe principal compositions sought to be patented.

The tangible embodiments of the principal compositions of the inventionpossess the inherent applied use characteristic of being intermediatesfor the production of valuable3-amino-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-Z-ones disclosed incopending US. application Ser. No. 187,983 filed Apr. 16, 1962, nowabandoned which have useful properties in that they are of value inveterinary and human medicine because they are themselves effectiveanticonvulsants, sedatives, and musclerelaxants and in addition areconvertible to anti-convulsants, sedative and muscle-r laxants of provenclinical utility.

The invention sought to be patented in a further composition aspect, isdescribed in the concept of a chemical compound having the molecularstructure of 2-(2- amino-Z-acetamido)-acetamidobenzophenone, forexample, 2-(2-amino-2-acetamido) acetamidobenzophenone and2(2-amino-2-acetamido) acetamido-S-chlorobenzophenone.

The tangible embodiments of the further composition of the inventionpossess the inherent general physical properties of being medium rangemelting, white crystalline solids; are substantially insoluble in water,and are soluble in polar solvents, such as lower aliphatic alcohols.Examination of the compounds produced according to the hereinafterdescribed process reveals, upon nuclear magnetic resonance spectraanalysis, data confirming the molecular structure hereinbefore setforth. For example the doublet peak of the methine proton is evident.The aforementioned physical characteristics, taken together with thenature of the starting materials and the mode of synthesis, positivelyconfirm the structure of the further compositions sought to be patented.

The manner and process of making and using a specific embodiment of theinvention will now be generally described so as to enable a personskilled in the art of chemistry to make and use the same as follows:

The new processes of our invention are illustrated schematically for aspecific embodiment thereof, in the attached drawing.

The preparation of the starting materials for the processes of ourinvention such as 2-[2-(N-acyloxyacylamido) acetamido]benzophenone (I)is described in copending US. application Ser. No. 283,966 filed May 29,1963, now abandoned and in Ser. No. 327,667 filed Dec. 3 1963, nowabandoned, i.e., by acylating 2- (Z-hydroxyaminoacetamido)benzophenonewith acylating agents such as, but not limited to, acetic anhydride,acetyl chloride, isopropenyl acetate (ketene), ethyl chloroformate,t-butoxy-pnitrophenyl carbonate, carbo-terL-butoxyazide, the 2-(2-hydroxyaminoacetam'ido)benzophenone having been prepared by treatment ofthe appropriate 2-(2-haloacetamido) benzophenone with hydroxylamine asdescribed in copending US. application Ser. No. 301,771 filed Aug. 13,1963, now abandoned.

A 2-[2 (N acyloxyacylamido) acetamidoJbenzophenone (I) upon treatmentwith ammonia surprisingly and unexpectedly undergoes a unique reactionwhich apparently involves an elimination of an acyloxy moiety, ad ditionof ammonia, and ring closure; the elimination and addition proceeding ina unpredictable fashion and in a way contrary to that which the priorart indicates should occur.

The reaction is performed at room temperature by treating a solution ofthe starting compound with alcoholic solvent saturated with ammonia gas.Similarly, concentrated ammonium hydroxide-dimethoxy ethane,concentrated ammonium hydroxide-ethanol, and liquid ammonia also givegood yields. The reaction can be conducted in any dispersion in an inertliquid phase, and is not limited to liquids in which the startingcompounds are soluble; and, liquid ammonia can be used without anotherliquid. While the rate of reaction appears to be rapid, to insure goodyields the reaction mixture is allowed to stand for several hours. Thetemperature at which the reaction occurs is not critical but it shouldnot be so high as to cause decomposition of the desired end product.However, if the reaction is performed at room temperature or below andthe crude product isolated by removal of the solvent is not permitted tostand, the intermediate 2-(Z-aminO-Z-acetamido)-acetamido benzophenonecan be isolated, and then converted to the cyclized benzodiazepin-Z-oneby dehydration.

Hydrolysis of a 3-acylamido-1,3-dihydro-5-phenyl-H-1,4-benzodiazepin-2-one (II) is preferentially performed in methanolcontaining a large excess of hydrogen chloride at room temperature.Other similar mild hydrolizing conditions can also be used, butconcentrations of strong hydrolizing agents which would open theheterocyclic ring of the desired product must be avoided. Thetemperature in this reaction is again not critical, but as in the ringclosure step, it should not be so high as to cause decomposition of thedesired end product. To insure good yields the hydrolysis reactionmixture is allowed to stand for several hours. Good yields are alsoobtained with concentrated hydrochloric acid provided the temperaturedoes not exceed C.

It will be apparent to those skilled in the art that certain of thecarbon and the bridging nitrogen atom of the 2-position of the startingbenzophenone can be substituted with non-interfering groups instead ofhydrogen atoms. Therefore, in the processes of the invention, except forthe limitations expressed in this specification, all 2-[2-(N-acyloxyacylamido)acetamido]aryl ketones can be employed as startingmaterials in the process of making aspect of this invention. Withoutlimiting the generality of the foregoing, the acetamido nitrogen can besubstituted with hydrogen, an alkyl group such as methyl, ethyl,isopropyl, an alkenyl group such as :allyl and rnethallyl or a loweraralkyl group such as benzyl or phenethyl; except that, when theacetamido nitrogen is substituted with hydrogen, the acyl of the N-acylamido group cannot be aryloxycarbonyl. Moreover there must be at leastone hydrogen atom at position -2 on the acetamido group for theformation of a Z-amino intermediate and cyclisation to be possible. Inthis specification, therefore, where the term acylamido or acetamido isused in connection with this group, it is defined as having at least onehydrogen atom at the said position -2.

In the aforementioned starting compounds, in general the acyl andacyloxy groups on the acyloxyacylamidonitrogen atom can be the same ordifferent; they can for instance be lower alkanoyl or lower alkanoyloxy,e.g., formyl, acetyl or propionyl, formyloxy, acetoxy or propionoxy;lower aroyl or aroyloxy, e.g., benzoyl or halobenzoyl, benzoyloxy orhalobenzoyloxy; or lower-aralkanoyl or lower-aralkanoyloxy, e.g.,phenylacetyl, phenylacetoxy.

The phenyl group bearing the Z-(N-acyloxyacylamido) acetamidosubstituent can have one or more substituents other than hydrogen, asfor example, but without limitation, lower alkyl, chlorine, bromine,trifiuoromethyl at the 3-, 4-, 5-, or 6-positions and such substituentsdo not interfere with the course of the reactions here involved. Thephenyl nucleus of the phenyl-keto group can bear one or more simplesubstituents inert to the reactions herein described, such as loweralkyl, chlorine, bromine, trifiuoromethyl, or methyl sulfonyl and suchsubstituted phenylketo compounds are full equivalents of theunsubstituted phenyl nucleus for the purposes of the present invention.

From the disclosure herein illustrating the invention as applied tostarting materials which produce compounds wherein the 5-positionsubstituent is phenyl or substituted phenyl, it will be apparent toorganic chemists that other mono-cyclic nuclei can be in the startingmaterials in lieu of phenyl without affecting the course of thereactions involve-d in the ring closure and the subsequent hydrolysis.Accordingly, such reactions wherein the phenyl group is replaced by 2-or 3-thienyl; 2- or 3-furyl; and 2-, 3- or 4-pyridylradicals are thefull equivalents of the invention as particularly claimed. Moreoverinstead of an aryl substituent, the phenyl substituent could be replacedby an alkyl substituent including the straight and branched-chainradicals, among which are for purposes of illustration but withoutlimiting the generality of the foregoing, methyl, ethyl, propyl,isopropyl, n-butyl, t-butyl, iso-amyl, and the cyclized alkyl radicalscyclobutyl, cyclopentyl, and cyclohexyl.

When the starting compounds are substituted as hereinbefore recited,itwill be apparentherefrom to those skilled in the art of chemistry thatthe intermediate com pounds and the final products formed by the processof invention will bear, correspondingly, the same substituents.

The following examples illustrate the best mode contemplated by theinventors of using the claimed processes of the invention and of themanner of making and using a specific embodiment of the claimedcompositions of the invention.

Example 1 To ml. of ethanol saturated with ammonia, add 1.0 g. of2-[Z-(N-acetoxyacetamido)acetamido]-5-chlorobenzophenone with stirring.Allow to stand for ca. 12-15 hours. Concentrate in vacuo and dissolvethe residue in benzene. Cool and allow to stand two to three days atabout 10 C. Collect as a white solid the precipitated 3-acetamido-7-chloro-1,3-dihydro 5-phenyl-2H-1,4-benzodiazepin-Z-one, M.P.272-273 C.

Example 2 Dissolve l g. of 3-acetamido-7-chloro-1,3-dihydro-5-phenyl-ZI-I-1,4-benzodiazepin-2-0ne in methanol containing excesshydrogen chloride. Allow to stand for 18 hours. Dilute the solution withwater and make it alkaline with ammonium hydroxide. Collect the solidwhich separates out and recrystallize from ethanol to obtain 3-an1ino-7-chloro-1,3-dihydro-5-phenyl-2H 1,4-benzodiazepin2-onc, M.P. 202203 C.

Example 3 By the procedure of Example 2, 7 chloro 1,3 dihydro 3formamido 5 phenyl 2H 1,4 benzodiazepin 2 one, M.P. 243-245 C. isconverted to 3 amino- 7 chloro 1,3 dihydro 5 phenyl 2H 1,4 benzodiazepin2 one.

Example 4 To 100 ml. of ethanol saturated with ammonia add 1.0 g. of 2[2 (N-acetoxyacetamido)acetamido] 5 chlorobenzophenone with stirring.Allow to stand for ca. 12- 15 hours. Concentrate in vacuo and dissolvethe residue in benzene. Cool Without permitting to stand, seed to obtain(2 amino 2 -'acetamido) acetamido 5 chlorobenzophenone. Rapidlyrecrystallize from acetonitrile to constant melting point -142 C.

Analysis for C H ClN O .-Calculated: C, 59.05; H, 4.67; N, 12.15; Cl,10.25. Found: C, 58.76; H, 4.40; N, 11.87; C1, 10.4.

Example 5 Add slowly a slurry of 2 g. of 2 [2(N-acetoxyacetamido)acetamido] 5 chlorobenzophenone in 20 ml. ofmethanol to 100 ml. of methanol saturated with ammonia at 5060 C. Heatat reflux temperature for 2.5 hours. Evaporate the solvent in vacuo anddissolve the residue in benzene. Cool and collect as a white solid 3acetamido 7 chloro 1,3 dihydro 5 phenyl 2H- 1,4 benzodiazepin 2 one,M.P. 272-273" C.

Example 6 To 2 l. of methanol saturated with ammonia at 25, add 1.5 l.of methanol and 70 g. of 2 [2 (N-acetoxyacetamido)acetamido] 5chlorobenzophenone and heat the resulting solution to 60 during 2 hours.Allow to reflux for 1% hours. Concentrate to 350 ml. at atmosphericpressure and cool to 40. Add 8.4 ml. of glacial acetic acid. Cool slowlywith stirring to 20 and stir for 4 hours. Chill to for 1 hour and filterand wash the filter cake with 3X20 ml. of methanol to afiord 38.4 g.(65%) of 3 acetarnido 7 chloro 1,3 dihydro phenyl 2H 1,4 benzodiazepin 2one, M.P. 272274 dec.

Example 7 To 50 ml. of cone. hydrochloric acid, add 10 g. of productfrom Ex. 6 in portions during 5 minutes at 25.

Allow to stir for 19 hours and cool to 15. Add 20 g. of ice, 120 ml. ofwater and cautiously add ml. of ammonium hydroxide (incompleteneutralization). Stir for 1 hr. at 10 and filter ofi 8.6 g. (87%) of 3amino 7 chloro 1,3 dihydro 5 phenyl 2H 1,4 benzodiazepin 2 onehydrochloride, M.P. 204-205 dec. Crystallization from water raises theM.P. to 211-212 for a total recovery of 71% based on the acetamidostarting material.

The subject matter which the applicants regard as their invention isparticulanly pointed out and distinctly claimed as follows:

1. 2 (2 amino 2 acetamido) acetamidobenzophenone.

2. 2 (2 amino 2 acetamido) acetamido-S-chlorobenzophenone.

References Cited UNITED STATES PATENTS 6/1964 Reeder et a1 260-562 OTHERREFERENCES NORMA S. MILESTONE, Primary Examiner.

NATALIE TROUSOF, Assistant Examiner.

